With its transparency, mechanical strength, and flexibility, polyvinyl chloride has been frequently used for the materials of medical tubes. Usually, a plasticizer, such as DEHP (diethylhexylphthalate), is incorporated in a polyvinyl chloride medical tube to impart flexibility. However, when the polyvinyl chloride tube comes in contact with blood or body fluids, the plasticizer is eluted from the tube. Such elution is considered problematic because it raises concerns including the influence of the eluted plasticizer on a living body and hardening of the tube over time. Meanwhile, there have been attempts regarding surface treatments of medical tubes in order to improve blood compatibility; however, it is difficult to surface-treat the medical tubes, considering the large amount of plasticizer in the tube.
To address these problems, plasticizer-free tube materials composed of an elastomer, tube materials composed of polybutadiene less likely to adsorb medicaments, and the like have been developed. However, these tube materials are inferior in kinking resistance compared with polyvinyl chloride tubes, and therefore break easily. Further, tubes composed of polyolefin materials such as polyethylene have a large impact resilience, which often decreases operability. Further, studies of ethylene-vinyl acetate copolymer, styrene-based elastomer and the like have also been conducted; however, the material costs are significantly higher for these materials than polyvinyl chloride.
On the other hand, there also have been attempts to solve the above problem using a multilayer structure of polyvinyl chloride and polyolefin materials. For example, Patent Document 1 discloses a multilayer tube comprising at least two layers, which includes a chlorinated polyethylene layer as an outer layer and a polyethylene resin layer as an inner layer. Kinking and warping of this multilayer tube do not occur when it is folded, the tube also has moderate flexibility, and there is no change in shape or size after sterilization. With such characteristics, this multilayer tube enables solvent welding with another tube having a different diameter or with injection-molded parts. However, because of the high production costs compared with the materials containing only polyvinyl chloride, this multilayer tube is not widely used.
Further, Patent Document 2 discloses a tri-layered tube comprising a vinyl chloride resin in the outer layer, a low-density polyethylene in the inner layer, and an ethylene-vinyl acetate copolymer in the adhesive layer. Because of the incorporation of a low-density polyethylene in the inner layer, this tri-layered tube is capable of solvent welding and is superior in flexibility. However, this multilayer tube is also not widely used because of the high production costs compared with the materials containing only polyvinyl chloride.
In recent years, there have been active studies of medical devices using various polymer materials, and the use of polymer materials is expected for blood filters, films for artificial kidneys, films for plasma skimming, catheters, films for artificial lungs, artificial blood vessels, films for preventing adhesion, artificial skin, and the like. In these uses, medical devices must have biocompatibility because artificial materials, which are foreign objects for the body, are brought into contact with body tissues and blood. When medical devices are used as a material that comes in contact with blood, (a) prevention of the blood coagulation system, (b) prevention of adhesion/activation of platelets, and (c) prevention of activation of the complement system are three important items for ensuring biocompatibility. In particular, when the medical device is used as a material that comes in contact with blood for a relatively short time, such as an extracorporeal circulation medical device (for example, artificial kidney or films for plasma skimming), it is generally important to prevent the activation of platelets or the complement system, i.e., the items (b) and (c) above, because an anticoagulant, such as heparin or sodium citrate, is used with the device.
Generally, a microphase-separated surface, a hydrophilic surface, in particular, a gelled surface to which a water-soluble polymer is bonded, are considered superior in (b) prevention of adhesion/activation of platelets, while a hydrophobic surface such as polypropylene is inferior (see Non-Patent Documents 1 and 2). A surface with a microphase-separated structure can exhibit desirable blood compatibility by being rendered into an appropriate phase separation state; however, since the condition for imparting appropriate phase separation is limited, it results in restrictions in use. Further, although adhesion of platelets is suppressed in the gelled surface to which a water-soluble polymer is bonded, problematic irregular variation in blood cell components (platelets) is often observed because of restoration of platelets or microthrombus activated on the material surface.
On the other hand, regarding (c) prevention of activation of the complement system, it is known that a surface having a hydroxy group such as cellulose or ethylene-vinyl alcohol copolymer has high activity, while a hydrophobic surface such as polypropylene has slight activity (see Non-Patent Document 3). Therefore, for example, when a cellulose-based material or a vinyl alcohol-based material is used for a medical tube, it will cause the activation of the complement system; however, if a hydrophobic surface such as polypropylene is used, it will cause the adhesion/activation of platelets.
Further, a medical device that comes in contact with living tissues or body fluid in addition to blood, such as a film for preventing adhesion or an implant material that is implanted into a living body for a long time, or a wound dressing material that comes in contact with a wound area (a wound area with peeling skin and a living body tissue exposed to the surface), is required to have a surface that is not acutely recognized as a foreign substance by a living body, and that must be easily removable from the living body (i.e., they must have non-adhesive surfaces). However, the adhesion of living body tissues to the surface occurs in medical devices composed of polyurethane or polytetrafluoroethylene, which have heretofore been used as the aforementioned medical materials. As a result, these materials are acutely recognized as foreign substances by a living body. For this reason, the performance of these materials has been considered insufficient. Further, although silicone is another material that ensures high biocompatibility, its particularly high detachability hinders secure adhesion to the base material. Thus, it has been difficult to adopt silicone to composite materials and the like.
Polyethyleneglycol (PEG) is another example of a medical material. PEG has significantly superior blood compatibility and has been actively studied to be applied to medical tools. However, because PEG is water-soluble, when PEG is used as a medical material, it is necessary to process PEG into a block copolymer or a graft copolymer with other polymers, thereby fixing it to the surface.
In addition, a known technique is to coat a blood-contact surface of a medical device with poly(2-methoxyethylacrylate), which is a biocompatible material, to render the surface antithrombogenic (see Patent Document 3). However, since this method uses methanol as a solvent for coating, there is a problem of toxic residual methanol.
Further, also known is the use of a water-soluble copolymer of polyethyleneglycol acrylate and acrylic acrylate upon immunoassay analysis for the protection of the solid-phase surface (see Patent Document 4). However, because this copolymer is water-soluble, the biocompatibility will not last long.
Furthermore, a known technique is to impart both desirable biocompatibility and water insolubility by copolymerizing a hydrophilic (meth)acrylate monomer containing a phosphorylcholine group having high biocompatibility, and a alkyl (meth)acrylate monomer having high hydrophobicity (see Patent Document 5). However, since this copolymer has the form of a rigid solid at room temperature, the coating film of this copolymer may peel off; moreover, the biocompatibility in terms of immunity of the copolymer is insufficient.
The applicant of the present invention has already suggested a water-insoluble (meth)acrylate copolymer that is applicable to the blood-contact surface of a medical device and expresses antithrombogenicity for a long period of time (Patent Documents 6 to 9). These documents disclose an antithrombogenic material composed of a copolymer containing polyethyleneglycol(meth)acrylate, which is a hydrophobic monomer, and alkyl (meth)acrylate, which is a hydrophilic monomer. However, these documents nowhere disclose the problems at the coating step inside a polyvinyl chloride medical tube containing a plasticizer, or a means for solving the problems.
Further, Patent Document 10 discloses an antithrombogenic material, which is a (meth)acrylate copolymer composed of hydrophobic (meth)acrylate and hydrophilic (meth)acrylate. This antithrombogenic material contains silicone (meth)acrylate and/or alkyl (meth)acrylate as hydrophobic (meth)acrylate. Further, Patent Document 10 discloses that it is preferable to use methanol, ethanol, or isopropyl alcohol as an organic solvent to be used for the coating of a medical device with the antithrombogenic material. However, use of these alcohols as a coating solvent may cause a problem of plasticizer elution from the polyvinyl chloride medical tube.
Further, Patent Document 11 discloses a technique using an antithrombogenic material containing, as an essential component, an ionic complex of organic cation and heparin (derivative). The antithrombogenic material is dissolved in tetrahydrofuran (THF), and the resulting coating solution is applied to coat the inner cavity of a polyvinyl chloride tube. Since this technique uses THF as a coating solvent, there is a concern of possible elution of a large amount of plasticizer.